Studies into the mechanism of V3-mediated neutralizing and cell fusion- inhibiting antibody escape of human immunodeficiency virus type 1 (HIV-1) reveal lack of antibody binding is not the reason for failure to block infectivity. It appears that distant-site mutations from the V3 domain convey cell-free infectivity and cell-to-cell fusion, despite the apparent binding of V3-specific antibody. These same isolates of HIV-1, which were also homologous to other closely related neutralization sensitive isolates of HIV-1 in their CD4-binding domain(s), were found to be resistant to a potent human monoclonal capable of inhibiting gp120-CD4 binding. Frequently, a V3-specific monoclonal antibody was found to bind by immunofluorescence assay to a completely sequence-unrelated strain or isolate of HIV-1. Longitudinal studies of HIV-1 acute seroconverters demonstrated that a single population of virus makes up the viremic phase shortly after infection. Although virus genomic variation occurs over the subsequent years, most patients continue to make a V3-specific response to the initiating virus population, suggesting either lack of an altered antigenicity despite genomic variation or humoral immune paralysis through cross-reactivity. Serum fractionation by idiotypic analysis revealed the presence of epitopic diversity of the CD4-binding domain(s) on the gp120 of HIV-1 and its heterogenity suggests that multiple conformational epitopes are involved in its structure. The potency, however, of antibodies to this region are low and appear not to undergo affinity maturation. Evidence was found of skewed kappa/lambda ratios, oligoclonal immunoglobulin profiles and antibody clonotypes, suggesting a clonal dominance of the B cells may occur during HIV-1 infection. This mechanism would serve to restrict the availability of new B cell clones during antigenic variation and may limit the breadth of effective vaccine or immune response.